Imine formation cyclization

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

Analogous to the selectivity observed for the conversion of 48 into 50, pyridyl 51 formed enamine 52 which underwent cyclization to give 4-pyridyl-substituted quinoline 53. Again, imine formation first occurs on the less hindered ketone and subsequent cyclization on the more reactive carbonyl occurred in high yield. ... 

Imine formation by reaction of aniline 58 and dione 49 under thermal conditions gave a mixture of imines. Cyclodehydration using PPA gave nearly a 1 1 mixture of isomers 59 and 60. These authors attempted thermal cyclization conditions (similar to Gould-Jacobs type conditions) to affect cyclization of this mixture and failed. Also, these authors reported difficulty in the clean formation of the imine. They observed large amounts of the A -acetyl compound presumably coming from fragmentation of the imine at the reported temperature... 

Skraup proposed a simple mechanism involving imine formation followed by an acid-mediated cyclization. Unfortunately the observed regioselectivity is not consistent with the proposed mechanism when, for example, electron-rich aniline 4 reacts with a, 3-unsaturated aldehyde 5 to give quinoline 6. ... 

Scheme 2.160. Imin-formation/radical-cyclization for the synthesis of pyrrolidines.

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

This approach to the five-membered pyrrole ring reacts an a-aminoketone with a P-ketoester. The mechanism will probably involve imine formation then cyclization via an aldol-type reaction using the enamine nucleophile. Dehydration leads to the pyrrole. Only the key parts of this sequence are shown below. 

The mechanism of imine formation is standard, as seen in the other examples. The cyclization reaction is then like the Mannich reaction, attack of an enol on to the iminium cation. This time though, the nucleophile is provided by the resonance effect from the phenol system. 

Intramolecular imine formation has also been successfully applied to the synthesis of bicyclic iV-sulfonylketeni-mines 105 and 97 (Scheme 27) <2002HCA1973, 1997JOC3625>. In these cases, cyclization occurs under either basic or acidic conditions from the primary iV-sulfonamides 200 and 201 in high yield. 

The Staudinger-aza-Wittig cyclization methodology for imine formation can also be applied to the synthesis of oxazolines under essentially neutral conditions.Thus, an azido ester such as 281 reacts with triphenylphosphine to give the oxazoline 283 in excellent yield. There was no evidence for cychzation at the benzoate presumably because cyclization to a five-membered ring is faster than... 

Shu and co-workers (35) identified 2-isobutyl-3,5-diisopropylpyridine, 2-pentyl-3,5-dimethylpyridine, and its dihydro derivative obtained under similar conditions. Sultan (29) confirmed the presence of 3,5-diethyl-2-propylpyridine in a model system consisting of butyraldehyde and ammonium sulfide. Our proposed mechanism of their formation (20) consists of three steps 1) aldol condensation of the starting aldehydes to 2,4-alkadienals, 2) imine formation with ammonia, and 3) subsequent cyclization and oxidation to corresponding pyridines. An alternate mechanism, suggested by Shu and co-workers (33), takes into consideration the isolated dihydro derivatives. Hwang and co-workers described another dihydro derivative (19, R = Bu, R = R" = Pr, R= H) (37). 

The gas phase acid-catalyzed synthesis of pyridines from formaldehyde, ammonia and an alkanal is a complex reaction sequence, comprising at least two aldol condensations, an imine formation, a cyclization and a dehydrogenation (9). With acetaldehyde as the alkanal, a mixture of pyridine and picolines (methylpyridines) is formed. In comparison with amorphous catalysts, zeolites display superior performance, particularly those with MFI or BEA topology. Because formation of higher alkylpyridines is impeded in the shape-selective environment, the lifetime of zeolites is much improved in comparison with that of amorphous materials. Moreover, the catalytic performance can be enhanced by doping the structure with metals such as Pb, Co or Tl, which assist in the dehydrogenation. 

As mentioned previously, the cyclization of phenethyl ketone oximes with [Bu4N]Re04 and CF3SO3H and the cyclic imine formation from 0-sulfonyl oximes both proceed by intramolecular S 2-type reaction on the nitrogen atom of the oximes (Scheme 33). ° In contrast, both of the E- and Z-isomers cyclized smoothly and only 8-hydroxyquinoline was obtained regioselectively without forming 6-hydroxy derivatives. These phenomena are not consistent with a nucleophilic substitution reaction, and the cyclization of 0-2,4-dinitrophenyloxime 80a seemed to proceed by another reaction pathway (Scheme 37). To check isomerization of the 0-2,4-dini-trophenyloxime 84, the Z-isomer was treated with NaH and m-cresol. The isomerization of (Z)-84 hardly occurred, but 4-phenylbutan-2-one azine (85) and 4-phenyl-2-butanone (86) were obtained in 27 and 11%... 

Although cyclization can take place in many ways, according to Kallen [11] the most preferred pathway involves imine formation followed by intramolecular cyclization. During the course of cyclization a new chiral center at C-2 is created thereby giving rise to a diastereomeric mixture namely 2R, 4R and 2S, 4R. An interesting situation arises when the reactant aldehyde is also chiral. The stereochemistry at the newly formed center is controlled by the stereochemistry of the aldehyde [12]. In view of the biological importance of thiazolidine, Patek et al. reported a solid-phase synthesis protocol (Scheme 4) [13]. This enables the synthesis of compound libraries for quick lead optimization. 

From halides. Halides are easily converted into selenides. Since halides are also suitable radical precursors, this transformation is usually done when side reactions of halides with nucleophiles can occur. An example of this type is reported in Eq. (1). The bromide 5 was converted into a phenyl selenide, which could stand DIBALH reduction and imine formation. Tin mediated cyclization of 6 afforded the cyclopentylamine 7 in 72% yield [5]. 

Preparative Methods the commercial glycine Wmethylamide hydrochloride is converted to the racemic imidazolidinone (2) by imine formation with Pivalaldehyde and cyclization under acidic conditions (eq 1). The mandelate salt of like configuration is less soluble and is used for highly efficient resolution subsequent treatment with Boc anhydride (Di-t-butyl Dicarbonate) gives the enantiomeric Boc-BMI (1) (eq 2). 

The pathway involving cyclization of a protonated migrating group provides a very appealing alternative to the fragmentation-recombination pathway. Given the lack of evidence for imine formation, it is interesting to note that the formation of a protonated imine (14-H ) in the model system can alternatively arise formally as the result of removal of a hydride ion from the parent (saturated) system (12), aminopropyl (path e. Scheme 9). 

The second reaction starts with nucleophilic attack by the amine on the more electrophilic carbonyl group - the ketone. Imine formation is followed by cyclization and this second step is i normal nucleophilic substitution at the carbonyl group of an ester (Chapter 12). The imine double bond moves into the ring to secure conjugation with the ester. 

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